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Home , Antibody, Autoantibody, Autoimmune disease, Autoimmunity

Tests for Autoimmune Test Codes 249, 16814, 19946

Frequently Asked Questions

Panel components may be ordered separately. Please see the Quest Diagnostics Test Center for ordering information. 1. Q: What are autoimmune diseases? A: “Autoimmune ” refers to a diverse group of disorders that involve almost every one of the body’s organs and systems. It encompasses diseases of the nervous, gastrointestinal, and endocrine systems, as well as skin and other connective tissues, eyes, , and blood vessels. In all of these autoimmune diseases, the underlying problem is “”—the body’s becomes misdirected and attacks the very organs it was designed to protect.

2. Q: Why are autoimmune diseases challenging to diagnose? A: Diagnosis is challenging for several reasons: 1. Patients initially present with nonspecific symptoms such as , and muscle pain, , and/or weight change. 2. Symptoms often flare and remit. 3. Patients frequently have more than 1 . According to a survey by the Autoimmune Diseases Association, it takes up to 4.6 years and nearly 5 doctors for a patient to receive a proper autoimmune disease diagnosis.1

3. Q: How common are autoimmune diseases? A: At least 30 million Americans suffer from 1 or more of the 80 plus autoimmune diseases. On average, autoimmune diseases strike three times more women than men. Certain ones have an even higher female:male ratio. Autoimmune diseases are one of the top 10 leading causes of death among women age 65 and under2 and represent the fourth-largest cause of disability among women in the United States.3 Women’s enhanced immune system increases resistance to , but also puts them at greater risk of developing autoimmune disease than men. Autoimmune disease commonly occurs in multiple members of a family, indicating a genetic predisposition. Family members are affected by various autoimmune disorders rather than one specific disorder.

4. Q: What is the first test to be considered for a patient suspected of having an autoimmune disease? A: When evaluating a patient for autoimmune disease, an antinuclear (ANA) test is typically performed first. The (IFA) (test code 249) screens for approximately 150 , which can occur in various autoimmune diseases. The American College of (ACR) recommends IFA as the gold standard method for ANA testing.4 A negative ANA IFA result suggests ANA-associated autoimmune diseases are not present. A positive result suggests the presence of autoimmune disease, and reflexes to titer and pattern. A low ANA titer (1:40 to 1:80) is consistent with preclinical disease or lack of disease. Titers >1:80 are consistent with autoimmune disease. In these cases, the staining pattern helps predict the disease type; however, specific antibody testing can be considered useful if clinically indicated. Frequently Asked Questions

5. Q: What is the significance of ANA patterns? A: The significance of various patterns is shown below.

Antibody Pattern Interpretation Nuclear Patterns Nuclear membrane Associated with autoimmune disease, including primary biliary (nuclear laminae, rim) and autoimmune ; also associated with SLE, Sjögren syndrome, and seronegative Associated with the CREST syndromea or Raynauda syndrome Homogenous Consistent with presence of to native DNA, histones, and/or deoxyribonucleoprotein; associated with SLE and drug-induced Nucleolar Suggestive of systemic sclerosis (), SLE, Sjögren syndrome, , overlap syndromes, or Raynaud phenomenon Proliferating nuclear Highly specific for SLE (PCNA) Speckled Suggestive of antibodies to RNP, SS-A, SS-B, Sm, centromere, p95 or p80 coilin; associated with mixed disease, SLE, Sjögren syndrome, , and systemic sclerosis/polymyositis overlap Nuclear dots (1-6 per cell) Consistent with Sjögren syndrome, SLE, systemic sclerosis, polymyositis, and asymptomatic individuals Nuclear dots (6-20 per cell) Consistent with primary biliary cirrhosis, polymyositis/dermatomyositis, and other systemic autoimmune rheumatic diseases Cytoplasmic Patterns Cytoskeletal Associated with autoimmune (anti-); , Crohn disease, and long-term hemodialysis; alcoholic liver disease, , and (anti-) Consistent with SLE, Sjögren syndrome, cerebellar disease, and viral Lysosomal Unknown clinical significance Mitochondrial Suggestive of antimitochondrial antibody presence and primary biliary cirrhosis Ribosomal Unknown clinical significance; may be associated with neuropsychiatric lupus SLE, systemic ; RNP antibody, ribonucleoprotein antibody; SS-A, SS-B antibodies, Sjögren syndrome antibodies A and B; and Sm antibody, Smith antibody. a CREST is a syndrome defined by presence of calcinosis, Raynaud phenomenon, esophageal dysmotility, , and telangiectasia.

Note: At Quest Diagnostics each pattern is reported if more than one is observed. Frequently Asked Questions

6. Q: Can I use one patient specimen to both screen and test for specific antibodies? A: Yes, Quest Diagnostics offers test code 16814 (ANA Screen, IFA, Reflex Titer/Pattern and Reflex to Multiplex 11 Ab Cascade). This test begins with an ANA screen using IFA technology. A positive result reflexes to titer and pattern and to a 3-tiered, 11-antibody cascade. The first tier includes chromatin, dsDNA, RNP, Sm, and Sm/RNP antibodies. If all 5 antibodies are negative, testing proceeds to the second tier, which includes Jo-1, Scl-70, SS-A, and SS-B antibodies. If all 4 of these antibodies are negative, testing proceeds to the final tier, which includes centromere B and ribosomal P antibodies. Figure 1 details the cascade and interpretation of specific antibody results. Note that if the ANA IFA result is positive but all 11 specific antibody results are negative, an autoimmune disease may still be present. The disease may be associated with an antibody not tested for in the cascade. Diseases to be considered include rheumatoid arthritis, , primary biliary cirrhosis, autoimmune , Addison disease, pernicious , autoimmune neuropathies, , celiac disease, bullous disease, and others.

7. Q: Can I order specific antibody testing without an ANA (IFA) screen? A: The ANA Multiplex with Reflex to 11 Antibody Cascade (test code 19946) can be used. This test does not include an ANA screen based on IFA technology. This less sensitive, but more specific test uses multiplex bead technology. The test includes a 3-tiered, 11-antibody cascade that begins with chromatin, dsDNA, RNP, Sm, and Sm/RNP antibodies. If all 5 antibodies are negative, testing proceeds to the second tier, which includes Jo-1, Scl-70, SS-A, and SS-B antibodies. If all 4 of these antibodies are negative, testing proceeds to the final tier, which includes centromere B and ribosomal P antibodies. A negative result on all 11 antibodies does not rule out autoimmune disease. A disease associated with an antibody not tested in the cascade may be present, especially if the patient has previously tested positive on an ANA IFA screen. Diseases to be considered include rheumatoid arthritis, autoimmune hepatitis, primary biliary cirrhosis, , Addison disease, pernicious anemia, autoimmune neuropathies, vasculitis, celiac disease, bullous disease, and others.

8. Q: How predictive are the specific antibodies? What is their sensitivity and specificity in various autoimmune diseases? A: Presence of a specific antibody is highly suggestive for the associated autoimmune disease. However, these antibodies are not specific for a particular disease; thus, results need to be interpreted in context of the clinical information and the following antibody prevalence.

Prevalence of Tier 1 Antibodies5-8 • Double-stranded DNA (dsDNA) antibodies are present in 57% to 62% of systemic lupus erythematosus (SLE) cases, 10% to 43% of polymyositis, 11% to 20% of Sjögren syndrome, 8% of systemic sclerosis (scleroderma), and 0% to 8% of mixed connective tissue disease (MCTD). • Chromatin antibody is present in >80% of MCTD cases, 37% to 73% of SLE, 14% of systemic sclerosis, 12% of Sjögren syndrome, and 8% of polymyositis. • Ribonucleoprotein (RNP) antibodies target RNP A and/or RNP 68kD ; antibodies to one or both are present in >80% of MCTD cases, 22% to 48% of SLE, 14% of systemic sclerosis, 12% of Sjögren syndrome, and 8% of polymyositis. Frequently Asked Questions

Figure 1. Use of ANA (IFA) and Specific Antibody Testing Cascade (Test Code 16814) for the Diagnosis of Rheumatic Disease

ANA Screen (IFA)

Negative Positive

Tier 1 Rheumatic Titer and Pattern disease highly Chromatin, dsDNA, RNP, Sm, and Sm/RNP antibodies unlikely See Question 5 for pattern interpretation Negative Positive

Tier 2 Antibody Systemic Lupus Mixed Connective Test Erythematosus Tissue Disease Jo-1, Scl-70, SS-A, and SS-B antibodies dsDNA + (high specificity) – Chromatin + (high sensitivity) – Sm + (high specificity) – Negative Positive Sm/RNP + + (high titer) RNP + + (high titer) Tier 3 Centromere B and Antibody Sjögren Systemic Polymyositis ribosomal P antibodies Test Syndrome Scleroderma SS-A + – – SS-B + – – Negative Positive Scl-70 – + – Jo-1 – – + No evidence of rheumatic disease shown Antibody CREST Neurologic by analytes tested Test Syndrome SLE Centromere B + – Ribosomal P – +

The acronym CREST refers to a syndrome defined by presence of calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia. dsDNA indicates double-stranded DNA; Sm/RNP antibody, Smith/ribonucleoprotein antibody; SS-A and -B antibodies, Sjögren syndrome A and B antibodies; Scl-70 antibody, scleroderma (topoisomerase I) antibody; Jo-1 antibody, histidyl-tRNA synthetase antibody; and SLE, systemic lupus erythematosus. This figure was developed by Quest Diagnostics based on references 1-5. It is provided for informational purposes only and is not intended as medical advice. A physician’s test selection and interpretation, diagnosis, and patient management decisions should be based on his/ her education, clinical expertise, and assessment of the patient. References 1. Kavanaugh A, Tomar R, Reveille J, et al. Guidelines for clinical use of the antinuclear antibody test and tests for specific autoantibodies to nuclear . Arch Pathol Lab Med. 2000;124:71-81. 2. Satoh M, Chan EKL, Sobel ES, et al. Clinical implication of autoantibodies in patients with systemic rheumatic diseases. Expert Rev Clin Immunol. 2007;3:721-738. 3. Stinton LM, Fritzler MJ. A clinical approach to testing in systemic autoimmune rheumatic disorders. Autoimmun Rev. 2007;7:77-84. 4. Petri M, Orbai AM, Alarcón GS, et al. Derivation and validation of systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012;64:2677-2686. 5. Cappelli S, Randone SB. “To be or not to be,” ten years after: evidence for mixed connective tissue disease as a distinct entity. Semin Arthritis Rheum. 2012;41:589-598. Frequently Asked Questions

8. Q: How predictive are the specific antibodies? What is their sensitivity and specificity in various autoimmune diseases? (continued) • Sm/RNP antibodies are directed to formed in a complex of Sm and RNP; antibodies to the Sm/RNP complex are present in 54% to 94% of MCTD cases, 30% of SLE, 4% of systemic sclerosis, and 9% of Sjögren syndrome and polymyositis. • Sm antibody is present in 20% to 30% of SLE cases, 8% of MCTD, 10% of polymyositis, 0% of systemic sclerosis, and 4% of Sjögren syndrome. Double stranded DNA, chromatin, ribonucleoprotein, Sm/RNP complex and Sm antibodies are also present in <2% of normal blood donors.

Prevalence of Tier 2 Antibodies7,8 • SS-A and SS-B antibodies are present in >80% of Sjögren syndrome cases and are considered a diagnostic indicator for this autoimmune disease. However, these antibodies are also present in other autoimmune disorders. SS-A antibodies are seen in 33% to 52% of SLE cases, 42% of polymyositis, 23% of systemic sclerosis (scleroderma), and 13% of MCTD. SS-B antibody is present in 13% to 27% of SLE cases, 5% of systemic sclerosis, <2% of polymyositis, and <2% of MCTD. • Scl-70 antibody is present in 16% of systemic sclerosis cases, 7% of MCTD (especially those with features of systemic sclerosis), 2% to 3% of SLE, <2% of Sjögren syndrome, and <2% of polymyositis. • Jo-1 antibody is present in 17% of polymyositis cases, 7% of MCTD (especially in those with features of muscle ), <2% of SLE, Sjögren syndrome, and systemic sclerosis. Tier 2 antibodies are also present in <2% of normal blood donors.

Prevalence of Tier 3 Antibodies7-10 • Centromere B antibody is present in 27% of systemic sclerosis (scleroderma) cases, 66% of CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia), 3% to 12% of SLE, 7% of MCTD (typically with features of polymyositis), and <2% of Sjögren syndrome, polymyositis, and normal blood donors. • Ribosomal P antibody is present in 9% to 30% of SLE cases (often with neurological manifestations), 7% of MCTD, and <2% of Sjögren syndrome, systemic sclerosis, polymyositis, and normal blood donors.

Note The prevalences listed above may vary with the population studied and methods used.5 Values given are for general guidance. Frequently Asked Questions

REFERENCES 1. Autoimmune disease in women. American Autoimmune screening and confirmatory testing.Clin Chem Lab Med. Related Diseases Association, Inc. Web site. http://www. 2015;53:1991-2002. aarda.org/autoimmune-information/autoimmune-disease-in- 6. Colglazier CL, Sutej PG. Laboratory testing in the rheumatic women/. Accessed February 4, 2016. diseases: a practical review. South Med J. 2005;98:185-191. 2. Walsh SJ, Rau LM. Autoimmune diseases: a leading cause of 7. Moder KG, Wener MH, Weisman MH, et al. Measurement death among young and middle-aged women in the United of antinuclear antibodies by multiplex immunoassay: a States. Am J Public Health. 2000;90:1463-1466. prospective, multicenter clinical evaluation. J Rheumatol. 3. Autoimmune diseases fact sheet. Womenshealth.gov Web site. 2000;34:978-986. http://www.womenshealth.gov/publications/our-publications/ 8. Binder SR, Genovese MC, Merrill JT, et al. Computer-assisted fact-sheet/autoimmune-diseases.html?from=AtoZ. Updated pattern recognition of autoantibody results. Clin Diagn Lab July 16, 2012. Accessed February 4, 2016. Immunol. 2005;12:1353-1357. 4. American College of Rheumatology Position Statement: 9. Mouthon L, Dunogue B, Guillevin L. Diagnosis and classification Methodology of testing for antinuclear antibodies. http:// of eosinophilic granulomatosis with polyangiitis (formerly www.rheumatology.org/Portals/0/Files/Methodology%20 named Churg-Strauss syndrome). J Autoimmun. 2014;48- of%20Testing%20Antinuclear%20Antibodies%20Position%20 49:99-103. Statement.pdf. Published January 2009. Updated August 2015. Accessed February 3, 2016. 10. Tur BS, Süldür N, Ataman S, et al. Anti- cytoplasmic antibodies in patients with rheumatoid arthritis: clinical, 5. Scholz J, Grossmann K, Knütter I, et al. Second generation biological, and radiological correlations. Joint Bone Spine. analysis of antinuclear antibody (ANA) by combination of 2004;71:198-202.

This FAQ is provided for informational purposes only and is not intended as medical advice. A physician’s test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient.

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